Egr-1 expression during neointimal development in flow-associated pulmonary hypertension.

ABSTRACT

In flow-associated pulmonary arterial hypertension (PAH), increased pulmonary blood flow is an essential trigger for neointimal formation. Using microarray analysis, we recently found that the early growth response protein 1 (Egr-1) transcription factor is increased in experimental flow-associated end-stage PAH. Its role in PAH development is unknown. Here, we assessed the spatiotemporal expression of Egr-1 during neointimal development in flow-associated PAH. Flow-associated PAH was produced in rats by combining monocrotaline administration with an aortocaval shunt. Animals were sacrificed 1 day before or 1 day, 1 week, or 4 to 5 weeks after flow addition. Egr-1 expression was spatiotemporally assessed using laser microdissection, quantitative real-time PCR and immunohistochemistry. In addition, Egr-1 expression was assessed in a non-neointimal pulmonary hypertension model and in human PAH associated with congenital shunt. In 4 to 5 weeks, rats subjected to increased flow developed PAH with neointimal lesions. Egr-1 mRNA was increased 1 day after flow addition and in end-stage PAH, whereas monocrotaline only did not result in increased Egr-1 mRNA. Directly after flow addition, Egr-1 was expressed in endothelial cells. During disease development, Egr-1 protein expression increased and migrated throughout the vessel wall. In PAH patients, Egr-1 was expressed in vessels with media hypertrophy and neointimal lesions, including plexiform lesions. Thus, Egr-1 may be an important regulator in the development of pulmonary neointimal lesions induced by increased pulmonary blood flow.